Paracetamol (paracetamol, 1) is among most commonly used analgesics. It effectively reduces fever and mild-to moderate pain, and is regarded, in general, as a very safe drug. Nevertheless, overdose (deliberate) is a common cause of hepatic injury, accounting for ˜40% of cases of acute liver failure in the USA. [Wu, C. C. Nitric oxide and inflammation. Curr. Med. Chem.-Anti-inflammatory & anti-allergy agents, 2004, 3, 217-222; Joshi, G. P. NCX-701. NicOx. Curr. Opin. Investig. Drugs, 2004, 5, 755-759; and Moore, P. K.; Marshall, M. Nitric oxide releasing paracetamol (nitroparacetamol). Dig. Liver Dis., 2003, 35.] It is an effective analgesic and antipyretic agent and unlike other NSAIDs (Non-steroidal Anti-inflammatory Drugs) has been reported to have little anti-inflammatory effects. [Fiorucci, S.; Antonelli, E.; Mencarelli, A.; Palazzetti, B.; Alvarez-Miller, L.; Muscara, M.; del Soldato, P.; Sanpaolo, L.; Wallace, J. L.; Morelli, A. A NO-releasing derivative of paracetamol spares the liver by acting at several checkpoints in the Fas pathway. Br. J. Pharmacol., 2002, 135, 589-599.] It is metabolized in liver by three pathways-glucuronidation, sulfonation (both accounting for 95% of metabolism) or via cytochrome P450 enzyme system (5%) in which it is converted to a toxic metabolite (N-acetyl-p-benzoquinone imine, 2) which further is rendered harmless through an interaction with the endogenous antioxidant glutathione.

But overproduction of this toxic metabolite leads to depletion of glutathione stores in liver and further accumulation of the toxic metabolite causes tissue injury and cell death. [Futter, L. E.; al-Swayeh, O. A.; Moore, P. K. A comparison of the effect of nitroparacetamol and paracetamol on liver injury. Br. J. Pharmacol., 2000, 132, 10-12.] Numerous derivatives of paracetamol have been synthesized to get a safer non-hepatotoxic drug. One of the major achievements has been by Nocox in Italy. It has designed NCX-701 (3) by adding NO moiety to paracetamol, via an aliphatic spacer to improve the anti-inflammatory activity of paracetamol, based on the well-demonstrated activity of NO on cytokine synthesis and regulation of proinflammatory mediators. [Wallace, J. L. Paracetamol hepatotoxicity: NO to the rescue. Br. J. Pharmacol., 2004, 143, 1-2.]

NO may modulate spinal and sensory neuron excitability through multiple mechanisms that may improve the antinociceptive activity of paracetamol. The pharmacological profile of NCX 701 has been reviewed. [Marshall, M.; Moore, P. K. Effect of nitric oxide releasing paracetamol and flurbiprofen on cytokine production in human blood. Eur. J. Pharmacol., 2004, 483, 317-322; and al-Swayeh, O. A.; Futter, L. E.; Clifford, R. H.; Moore, P. K. Nitroparacetamol exhibits anti-inflammatory and anti-nociceptive activity. Br. J. Pharmacol., 2000, 130, 1453-1456]. Compared with NSAIDs, paracetamol possesses little anti-inflammatory activity in humans and it does not induce damage of the gastric mucosa, but it could cause liver damage (or even poisoning) when used in high dosage. The aim of coupling paracetamol with NO has, therefore, been to improve its anti-inflammatory activity, and also to exploit the cytoprotective properties of NO to reduce potential liver damage. Concerning safety, several studies have highlighted the liver sparing profile of NCX 701 compared to paracetamol. The beneficial protective effect on the liver has been supposed to be related to the fact that NO can reduce the synthesis of several pro-inflammatory cytokines. [Wallace, J. L. Paracetamol hepatotoxicity: NO to the rescue. Br. J. Pharmacol., 2004, 143, 1-2]. The anti-inflammatory activity related to NO release has been demonstrated in vitro and in vivo, [Marshall, M.; Moore, P. K. Effect of nitric oxide releasing paracetamol and flurbiprofen on cytokine production in human blood. Eur. J. Pharmacol., 2004, 483, 317-322; al-Swayeh, O. A.; Futter, L. E.; Clifford, R. H.; Moore, P. K. Nitroparacetamol exhibits anti-inflammatory and anti-nociceptive activity. Br. J. Pharmacol., 2000, 130, 1453-1456; AND, Paul Clark, M. J.; Howat, D.; Flower, R. J.; Moore, P. K.; Perretti, M. Nitroparacetamol (NCX-701) exhibits anti-inflammatory activity in the zymosan air pouch. Inflamm. Res., 2001, 50, S158] demonstrating that NCX 701 is not only a safer drug than paracetamol, but that it also possesses a wider action due to additive mechanisms. Several papers have compared the antinociceptive activity of NCX 701 versus paracetamol, [Romero-Sandoval, E. A.; Mazario, J.; Howat, D.; Herrero, J. F. NCX-701 (nitroparacetamol) is an effective antinociceptive agent in rat withdrawal reflexes and wind-up. Br. J. Pharmacol., 2002, 135, 1556-1562; Romero-Sandoval, A. E.; Del Soldato, P.; Herrero, J. F. The effects of sham and full spinalization on the antinociceptive effects of NCX-701 (nitroparacetamol) in monoarthritic rats. Neuropharmacology, 2003, 45, 412-419; and Gaitán, G.; Del Soldato, P.; Herrero, J. F. Low doses of nitroparacetamol or dexketoprofen trometamol enhance fentanyl antinociceptive activity. Eur. J. Pharmacol., 2003, 481, 181-188]. regularly showing the superiority of NCX 701. Moreover, sub-effective doses of NCX 701 have enhanced the anti-nociceptive activity of the μ-opioid receptor agonist fentanyl. A Phase II study clinical trial has demonstrated that 1 g NCX 701 provides similar analgesic efficacy to paracetamol 1 g in post-operative dental pain, therefore with a reduced exposure to paracetamol, confirming a contribution of NO to the anti-nociceptive mechanisms of NCX 701.
O-Dealkylation of a homologous series of alkoxy acetanilides [p-methoxy, p-ethoxy: phenacetin, p-(n)-propoxy- and p-(n)-butoxy acetanilides; 4-7] have shown to release paracetamol.
The compounds (6 and 7) were structurally related to phenacetin (5), and were synthesized to check whether they release paracetamol (1) upon O-dealkylation, which they did. The chain length in the synthesized compounds was varied to study the effect of chain lengthening on the rate of release of paracetamol.
[Chul-Ho, Y., Miller, G. P., Guengerich, F. P. Oxidations of p-Alkoxyacylanilides Catalyzed by Human Cytochrome P450 1A2: Structure-Activity Relationships and Simulation of Rate Constants of Individual Steps in Catalysist Biochemistry 2001, 40, 4521-4530]
The compounds (4, 6 and 7) are structurally related to phenacetin (5) therefore, on metabolism they will liberate paracetamol (1).
